With the discovery of BACE1 as the beta-secretase involved in the generation of beta-amyloid (Abeta) peptides in Alzheimer's disease (AD), we embarked on a series of studies to examine the functional roles of this transmembrane aspartal protease. We demonstrated that BACE1 is the principal beta-secretase in neurons and that it is essential to cleave APP to generate Abeta in the brain. Moreover, we have provided strong evidence to support our hypothesis that BACE1 and BACE2, along with APP are key determinants of selective vulnerability of brain to Abeta amyloidosis. Significantly, deletion of BACE1 in APPswe;PS1deltaE9 mice prevents both Abeta deposition and age-associated cognitive abnormalities that occur in this model of Abeta amyloidosis. In concert, these results suggest that inhibition of BACE1 should be effective in reducing the Abeta burden in AD. The overall goal is to evaluate critically BACE1 as a high priority therapeutic target for AD, particularly focusing on the reversibility of Abeta-induced abnormalities and the capacity of the brain for repair. In Aim 1, we will examine the role of BACE1 in the evolution of hypothesized Abeta related synaptic abnormalities in the perforant pathway by ultrastructural, immunocytochemical, and biochemical methods using APPswe-deltaE9 mice with varying gene dosage of BACE1. We then will examine in Aim 2 the reversibility of the structural and biochemical abnormalities in the perforant pathway by evaluating APPswe-PS1deltaE9 mice in which expression of BACE1 can be regulated via tet-off transgenic system or by lentiviral RNA interference methods. Results from our proposed studies will provide important information regarding the character and evolution of synaptic pathways, the reversibility of Ap-induced abnormalities, the capacity of the brain for repair in the perforant pathway, and the value of inhibition of BACE1 activity in efforts to ameliorate Abeta amyloidosis in AD.